This proposal for extended support is focused on the mechanisms and cell types by which the purinergic type 6 (P2Y6) receptor regulates the magnitude of allergen-induced type 2 immunity in the respiratory tract. P2Y6 receptor deletion sharply enhances pulmonary eosinophilic inflammation and type 2 cytokine generation in models of asthma induced by allergens from both the dust mite Dermatophagoides farinea and the mold Alternaria alternata. During the current period of support, we developed mice selectively lacking P2Y6 receptors on dendritic cells (DCs). Surprisingly, studies using these mice indicate that DC-associated P2Y6 receptors contribute only modestly to the protective effects observed in the global knockouts. Furthermore, our more recent studies suggest prominent expression of P2Y6 receptors by epithelial progenitor cells in the airways of patients with severe asthma. The studies going forward will use a combination of approaches in transgenic mice and human cells and samples to test the hypothesis that P2Y6 receptor signaling in epithelial progenitors controls type 2 immune responses through regulating cytokine secretion, epithelial repair, and tuft cell development. The studies should provide valuable information on the processes that regulate homeostasis in type 2 immunity that modifies the risk and severity of asthma. RELEVANCE (See instructions): This proposal seeks to understand how a molecule known as the P2Y6 receptor contrils the severity of inflammation in asthma. The studies should reveal potential factors that contribute to asthma severity and could lead to new therapies.